Preformulation Studies-2 Itm

UNIT-1
INDUSTRIAL PHARMACY-I
BP-502T
PREFORMULATION STUDIES
Part-3
BY- MRS. VIJETA B

ASSISTANT PROFESSOR
ITM UNIVERSITY
GWALIOR
PREFORMULATION STUDIES
Chemical Properties
“ Solubilization is defined as the spontaneous passage of

poorly water-soluble solute molecules into an aqueous
solution of a soap or detergent in which a
thermodynamically stable solution is formed ”.
2
1) Oxidation
2) Hydrolysis
3) Reduction
4) Racemization
5) Polymerization
Oxidation
The oxidative decomposition of pharmaceutical
compounds is responsible for the instability of a
considerable number of pharmaceutical formulations.
A substance is said to be oxidized if it-
 Gains electronegative atoms or radicals.
 Losses an electropositive atom or radical.
 Addition of oxygen.
 Removal of hydrogen
 Elimination of an electron.
Preventing Measures Against Oxidation
 Using Antioxidants (tocopherol), Chelating agents,
Buffers.
 . Antioxidants for Aqueous System:
Sodium sulfite, sod-metabisulfite, ascorbic acid & acetyl
systeine etc.
 . Antioxidants for Oil System:
BHA, BHT, Propyl gallate & Lecithin etc.
 . Buffer:
Phosphate, Citrate & Acetate Buffers etc.
 Maintain free oxygen environment.
 Storing products at low temperature, dark & cool place.
Hydrolysis
Hydrolysis is the common degradation pathway,
water plays an important role in solids &
solutions.
It is the cleavage of an ester & amide linkage of
the drug in the presence of water.
The cleavage of the chemical bond with solvents
other than water is known as ‘Solvolysis’.
Generally, it follows 2nd-order reaction kinetics but
if excess water is there, follows 1st-order reaction.
RCOOR + H+  RCOOH + HOR
Factor that Catalyses Hydrolysis
 Presence of Hydroxyl, Hydride and divalent

ions.
 Heat and light.
 High concentration of drug.
 Solution polarity and strength.
Prevention of Hydrolysis
Due to presence of moisture & catalytic spaces.
H+ & OH- prevented.
i) Buffers = For product stabilization.
ii)Complexing Agent = Prolong shelf life, form
complex with drugs, prevents hydrolysis.
iii)Suppression of Solubility = Less solubility
decrease conc. & decrease hydrolysis rate.
iv)Removal of Water = Presence of water avoided
by storing the drug in dry form.
Reduction
Common pathways of drugs metabolic process.
Hepatic microsomes catalyze diverse
reductive chemical reactions using
NADPH.
Cytochrome P450 catalyze the azo & nitro
reduction reaction.
The enzyme alcohol dehydrogenase catalyzes
reduction of chloral hydrate into trichloro ethanol.
Prednisolone & cortisone are reduced to
hydrocortisone.
Racemisation
Involves conversion of one enantiomer of a
compounds such as
L-Amino Acid, into other enantiomers.
. The compounds then alterats between each form
while the ration between (+) & (-) groups ratio 1:1.
. Occurs in mixture containing enantiomers in
equal quantities resulting sample of as
“racemic” & “racemate”.
It follows first order kinetics.
Examples: L-Epinephrine is 15-20 time more than
active D- Form activity of racemic mixture is half
of the L-form.
Polymerization
When surfactants are added to the liquid at
low concentration they tend to orient at
the air-liquid interface.
On further addition of surfactant, the interface becomes

completely occupied, and excess molecules are forced into
the bulk of the liquid.
At very high concentrations surfactant molecules in the

bulk of liquid begin to form micelles and this
concentration is known as CRITICAL MICELLE
CONCENTRATION {CMC}
Step 1: Holes opens in the solvent
Step2: Molecules of the solid breaks away from

the bulk
Step 3: The free solid molecule is intergraded into
the hole in the solvent
The amount of substance that passes into
the solution to establish equilibrium at constant
temperature and pressure to produce a saturated
solution.
If solubility is <1mg/ml indicates a
need for salt formation to improve solubility.
If solubility is <1mg/ml in pH= 1

to 7, a Preformulation study should be initiated.
Solubility should ideally be measured at two

temperatures: 4°C and 37°C.
4°C to ensure Physical stability.
37°C to support Biopharmaceutical evaluation.

Description Parts of solvent
required for one part
of solute
Very soluble <1
Freely soluble 1 - 10
Soluble 10 - 30
Sparingly 30 - 100
soluble
Slightly soluble 100 - 1000
Very 1000 - 10,000
slightly
soluble
Insoluble > 10,000
Ionization constant (pKa)
Can be calculated by Henderson
Hasselbach equation-
For acidic drugs….pH= pKa+ log [ionized

drug]
[unionized
drug]
For basic drugs….pH= pKa+ log[unionized

Partition Coefficient
It is the ratio of unionized drugs

distributed between the organic and aqueous phases
at equilibrium.
P o/w = ( C oil / C water )equilibrium

General Method of Increasing the Solubility
Addition of co-solvent
MONOSACCHARIDES
pH change method POLYSACCHARIDES
Reduction of particle size

Temperature change method
Hydotrophy
Addition of Surfactant
Dielectrical Constant
Complexation
Polymorphism
• The compound can crystallize as more than one
distinct crystalline species with different internal
lattices.
• Different crystalline forms are called polymorphs.
• Polymorphs are of 2 types

1. Enatiotropic
2. Monotropic
• The polymorph which can be changed from one
form into another by varying temp. or pressure is
called as Enantiotropic polymorph.
Eg. Sulfur.
• One polymorph which is unstable at all temp. &

pressure is called as Monotropic polymorph.
Eg. Glyceryl stearate.
• Polymorphs differ from each other concerning
their physical property such as
Solubility
Melting
point
Density
Hardness
Compression
characteristic

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UNIT-1

BY- MRS. VIJETA B

“ Solubilization is defined as the spontaneous passage of

 Presence of Hydroxyl, Hydride and divalent

On further addition of surfactant, the interface becomes

At very high concentrations surfactant molecules in the

Step2: Molecules of the solid breaks away from

If solubility is <1mg/ml in pH= 1

Solubility should ideally be measured at two

4°C to ensure Physical stability.

37°C to support Biopharmaceutical evaluation.

For acidic drugs….pH= pKa+ log [ionized

For basic drugs….pH= pKa+ log[unionized

It is the ratio of unionized drugs

P o/w = ( C oil / C water )equilibrium

Reduction of particle size

• Different crystalline forms are called polymorphs.

• Polymorphs are of 2 types

• One polymorph which is unstable at all temp. &

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